Abstract
Next-generation selective estrogen receptor-α (ERα) antagonist/degraders (SERDs) are being developed for ER-positive breast cancer (ER+ BC), with intentions of improving outcomes for patients. In recent clinical trials of metastatic ER+ BC, next-generation SERDs demonstrated clinical activity, and elacestrant received an approval for advanced ESR1-mutant disease. However, responses to these drugs were highly heterogeneous: across trials and independent of ESR1 status, 30–50% of patients progressed by their first follow-up scan while other patients sustained benefit for 2 years or more. Here, we interrogate the basis for heterogeneous responses by comparing biopsies from non-responding patients (NR; progression-free survival <2 months) and responding patients (Resp; PFS ≥ 2 months) who received the next-generation SERD giredestrant. While Resp tumors maintain high dependency on ERα signaling, NR tumors exhibit loss of luminal lineage identity and by extension, ERα dependence. NR tumors instead up-regulate multiple ERα-independent proliferative pathways, such as EGFR/MAPK and Hippo/TEAD, which may represent targetable dependencies in NR disease. Modeling resistance and lineage plasticity in vitro, we find that giredestrant-resistant ER+ BC cell lines exhibit profound shifts in chromatin accessibility, with the transcription factors, FOXA1 and FOXM1, implicated in gene expression of NR-upregulated proliferative pathways.
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Data availability
Raw and processed files from sequencing experiments have been uploaded to the NCBI Gene Expression Omnibus under the following accession IDs: GSE295127 (RNA-seq; www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295127), GSE295128 (ATAC-seq; www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295128), and GSE305432 (ChIP-seq; www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305432). Due to data privacy laws and the terms of informed consent for study GO39932, raw data from patient-derived F-ACT and RNA-seq cannot be deposited in a public repository nor made available upon request. The remaining data for Figs. 1–4 and all Supplementary Figs. have been provided as Source Data files. Source data are provided with this paper.
Code availability
Analysis code is available at https://doi.org/10.5281/zenodo.18644938. For ATAC-seq and ChIP-seq, all analysis code uses publicly available R packages. For RNA-seq, some analyses code includes custom in-house functions. The custom code was designed to analyze RNA-seq data within our institution’s cloud-based computing environment, and will not function properly outside of this environment. However, comparable analyses can be performed using publicly available R packages.
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Acknowledgements
We would like to thank Ann E. Collier, Alejandro Chibly, and Xiaosai Yao for helpful discussions; Meritxell Bellet, Sherene Loi, Aditya Bardia, Valentina Boni, Joohyuk Sohn, Tomas G. Neilan, Rafael Villanueva-Vázquez, Peter Kabos, Laura García-Estévez, Elena López-Miranda, Jose A. Pérez-Fidalgo, and Jose M. Pérez-García for providing biopsies in the clinical trial (NCT03332797); and patients for their participation in the clinical trial. This study was supported by funding from Roche/Genentech.
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J.L. designed/conducted the biomarker analyses and wrote the manuscript. J.L. & C.M. designed the experiments. K.H., C.O., & J.Guan performed the experiments. V.K. and B.D. performed the ChIP sequencing, M.S. and Y.L. performed the RNA and ATAC sequencing, J.Giltnane performed pathology review. H.M.M., J.A., C.-W.C., M.R.G., J.E.-W., P.P.-M., K.L.J, N.C.T, & E.L. conducted the clinical study. All authors reviewed the manuscript.
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The authors declare the following competing interests: excepting K.L. Jhaveri, N.C. Turner, and E. Lim, all authors are Genentech/Roche employees and own shares of Roche. C.M. is a named co-inventor on patent 11081236 entitled “Diagnostic and therapeutic methods for the treatment of breast cancer”. K.L. Jhaveri has a consultant/advisory board role in Novartis, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Genentech, Inc., AbbVie, Eisai, AstraZeneca, Blueprint Medicine, Daiichi Sankyo, Sun Pharma Advanced Research Company Ltd, Gilead, Seattle Genetics, Olema Pharmaceuticals, Menarini/Stemline, and Lilly/Loxo Oncology; and has received research funding from Novartis, Clovis Oncology, Genentech, Inc., AstraZeneca, ADC Therapeutics, Novita Pharmaceuticals, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals/Loxo Oncology, Zymeworks, Gilead, Puma Biotechnology, Context Therapeutics, and Merck Pharmaceuticals. N.C. Turner has received advisory board honoraria from AstraZeneca, Lilly, Pfizer, Roche–Genentech, Novartis, GlaxoSmithKline, Repare Therapeutics, Relay Therapeutics, Zentalis, Gilead, Inivata, Guardant, and Exact Sciences; and research funding from AstraZeneca, Pfizer, Roche–Genentech, Merck Sharpe & Dohme, Guardant Health, Invitae, Inivata, Personalis, and Natera. E. Lim reports research support from Ellipses, Novartis, and Pfizer; speaker compensation from AstraZeneca, Gilead, Novartis, Lilly, Pfizer and Roche; meeting and/or travel support from AstraZeneca, Novartis, and Gilead; advisory board compensation from AstraZeneca, Gilead, Lilly, MSD, Novartis, Pfizer and Roche; and leadership or fiduciary roles in the Breast Cancer Trials and University of New South Wales.
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Liang, J., Ong, C., Heslop, K. et al. Loss of luminal lineage drives resistance to next-generation ERα antagonists in pretreated ER+ HER2− locally-advanced or metastatic breast cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71233-1
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DOI: https://doi.org/10.1038/s41467-026-71233-1
